Low density lipoprotein-receptor like protein 1 (LRP) is a transmembrane protein that has been directly and indirectly implicated in Alzheimer's disease (AD). LRP binds the longer splice variants of the Alzheimer amyloid protein precursor (APP) (APP751 and APP770), which contain a Kunitz protease inhibitory (KPI) domain. LRP also binds apolipoprotein E (Apo E), and a2-macroglobulin (A2M). APP, Apo E and A2M have all been genetically and biochemically implicated in AD. Polymorphism in LRP may also be associated with AD, although with weak effect. The cytoplasmic domain of LRP binds the adaptor FE65, a protein that also binds APP and may also show weak genetic association with AD. Finally, recent evidence indicates that, like APP, LRP undergoes a presenilin mediated intramembranous cleavage in a process now known as regulated intramembranous proteolysis (RIP). Presenilin is genetically and biochemically linked to AD and is directly involved in the formation of Abeta. In spite of the genetic and biochemical evidence for a role for LRP in AD-related proteins and processes, several questions remain unanswered. First, it is not clear whether the interactions between APP, Apo E or A2M and LRP stimulate a signal-transduction cascade through RIP that may affect cell function. Second, the degree to which LRP-interacting proteins can modulate APP processing and function is not fully understood. Finally, it remains obscure as to whether modulating such interactions may represent a therapeutic target in AD. In this Project, we will examine these questions, primarily focusing on dissecting the functional significance of the interactions between LRP and APP, Apo E, A2M, and FE65. Understanding the functional significance of these interactions will allow us to better understand the biochemical (and perhaps genetic) role of LRP in AD. Furthermore, such studies may contribute to our understanding of the biochemical (and perhaps genetic) role of the LRP interactors in AD. Finally, such studies may identify therapeutic targets in AD. We will also work with other Projects to elucidate the role of LRP in Abeta clearance and in statin effects. The central hypotheses of the current project are that LRP modulates APP metabolism, Abeta formation and clearance, and cell function contributing to Alzheimer's disease, and that LRP ligands mediate these effects. The specific aims of this proposal are: To characterize the effects of ligands of LRP on LRP localization and processing; To elucidate the effects of LRP on APP localization and processing, as well as Abeta formation; To dissect the cytoplasmic/nuclear complex of LRP that is involved in signaling and in modulating APP processing.; To identify genes that are regulated by the cytoplasmic/nuclear complex of LRP; To examine the function of LRP in neuronal differentiation in vivo; and, To define the role of LRP in the clearance and catabolism of Abeta in vivo.